Design, Synthesis, and Biological Evaluation of Potent 20SProteasome Activators for the Potential Treatment of ?-Synucleinopathies

While neurodegenerative diseases affect millions ofpatients worldwide, there are insufficient available therapeutics tohalt or slow down the progression of these diseases. A keypathological feature of several neurodegenerative diseases is theoligomerization and aggregation of specific intrinsically disorderedproteins (IDPs) creating neuronal deposits, such as Lewy bodies inParkinson's disease. Clearance of these pathogenic, aggregation-prone IDPs is mediated by the 20S isoform of the humanproteasome. Thus, enhancing the 20S proteasome-mediatedproteolysis could be a very useful therapeutic pathway to preventneurotoxicity. Here, we report the successful development of sub-microM 20S proteasome activators based on a phenothiazine scaffold. This class of compounds prevented the accumulation ofpathologically relevant IDPs, such as the pathogenic A53T mutated alpha-synuclein,in vitroand in mammalian cell lines.